There are two long-read sequencing (LRS) platforms that support direct detection of modified bases from single molecule strands without the use of chemical treatment (e.g. bisulfite conversion). Both the Oxford Nanopore Technologies suite of platforms and the PacBio Revio leverage raw electrical signals or polymerase kinetics, respectively, to detect 5-methylcytosine (5mC), 6-methyladenine (6mA), and 5-hydroxymethylcytosine (5hmC) from sequencing reads where genomic DNA is used to make a library.  After a DNA sequencing run, users can assess both the DNA sequence (whole genome information) and modifications from each molecule at single nucleotide resolution at no additional cost to the user!  The use of LRS to detect modified bases enables resolution across large and complex regions of the genome and can be performed at genome-scale by increasing sequencing depth. 

Applications include native methylation calls (5mC, 5hmc) and 6mA calls for modified applications such as Fiber-seq and DiMeLo-seq.